Composition containing at least one C7 sugar for alopecia treatment, cosmetic treatment of hair and nails, and care of hair, eyelashes or nails

ABSTRACT

The present invention relates to a composition including at least one C7 sugar, or derivative from esterification of said sugar, and a pharmaceutically acceptable carrier for treating alopecia. The present invention also relates to a method for cosmetically treating hair and nails, said method being intended to stimulate the growth thereof and/or slow the loss thereof. According to said method, a cosmetic composition including at least one C7 sugar, or derivative from esterification of said sugar, is administered. The present invention finally relates to a method for cosmetic care of hair and/or eyelashes and/or nails.

This application is a continuation of U.S. patent application Ser. No.13/516,333, filed Sep. 4, 2012, which is a U.S. National Stage ofPCT/EP2010/069806, filed Dec. 15, 2010, which claims priority to FrenchApplication No. 0959075, filed Dec. 16, 2009, all of which are herebyincorporated by reference in their entirety.

The present invention relates to the use of C7 sugars in a compositionfor the care of hair and nails, intended to induce and/or stimulate thegrowth thereof and/or to slow the loss' thereof.

In particular, the invention relates to the use of C7 sugars to treatalopecia.

Hair growth and renewal are principally determined by the activity ofhair follicles and their matrix environment.

Hair is alive and follows a natural growth cycle, sometimes referred toas the hair growth cycle. This cycle is divided into three phases:anagen, catagen and telogen.

The anagen phase is the growth phase of the hair, and is the longestpart of the hair growth cycle since it lasts from two to five years. Thevery great majority of hairs are thus in anagen phase.

The catagen phase is a rest phase during which the hair ceases growing.It lasts approximately three weeks, which is quite short in relation tothe preceding phase.

The telogen phase, finally, leads after about three months to the deathand shedding of the hair, which will make room for a new follicle inanagen phase.

The number of hair growth cycles is limited: the hair goes through only25 to 30 cycles during its entire life. Since these cycles last from twoto five years; humans have quite enough hair growth cycles,theoretically, to maintain beautiful hair throughout their lives.

Unfortunately, for various reasons, including an inflammatory reactionexacerbated at the hair follicle, the duration of these cycles candecrease considerably and lead to total exhaustion of capillarypotential in only a few years. The hair then starts by becomingincreasingly thin, leading to baldness.

Hair loss is accompanied, as is now known, by inflammation at the root.Inflammation leads to the destruction of hair follicles and thedevelopment of scar tissue. Pro-inflammatory cytokines have shown to becapable of inhibiting in vitro the growth of isolated hair folliclesplaced in culture.

Alopecia is a loss of hair on all or part of the scalp. On average, 60hairs per day are lost naturally. There are seasonal variations, withgreater loss in the spring and autumn. However, a loss of more than 100hairs per day is always excessive. Especially if it persists, the lossbecomes abnormal and must be treated.

Alopecia affects roughly 20% of 20-year-old men and increases by roughly10% every 10 years. In men, hair loss results in balding of gulfs andthe top of the head. It is progressive and foreseeable. Slightly morethan half of all men over 50 have some degree of baldness.

Although baldness is a primarily male phenomenon, alopecia also affectsmore and more women. In women, an overall decrease in hair is observed,predominantly on the top of the head.

The term alopecia also covers a whole family of attacks on the hairfollicle, the eventual consequence of which is definitive, partial orgeneral hair loss.

Diffuse hair loss can be distinguished from localized hair loss. Diffusehair loss includes telogen effluvium, anagen effluvium, alopecia areata.Among causes of diffuse hair loss, the most frequent are common alopecia(male and female androgenic alopecia) and telogen effluvium (after ahigh fever, pregnancy, taking of medicine or a strict diet).

Localized hair loss includes androgenetic alopecia, alopecia areata,scarring alopecia and tumors. Localized hair loss is observed in thecontext of male androgenic alopecia (gulfs, tonsure), alopecia areataplaques, alopecia caused by pulling (trichotillomania, braids andstraightening) or scarring alopecia (central centrifugal cicatricialalopecia, post-menopausal frontal fibrosing alopecia). Tumors and skinexcrescences are also accompanied by localized hair loss (sebaceoushamartoma, basal-cell carcinoma, squamous-cell carcinoma).

It also appears that the presence of free radicals maintains tissueinflammation and promotes the aging of hair follicle cells. Thisinflammatory reaction is recognized as one of the causes of shorter hairlife.

Generally, alopecia appears on the scalp but it can also appear on theentire body. On bald plaques, roots produce only thin hair that fallsout rather quickly. The hair roots do not necessarily die followingalopecia. If the inflammation disappears, the hair can start to growagain, sometimes after months, or even after years. Alopecia can alsoaffect the nails.

The cosmetics and pharmaceutical industries have for many years soughtcompositions to eliminate or reduce alopecia, and notably to induce orstimulate growth of keratinous fibers, to include the hair, or todecrease their loss.

Accordingly, a large number of compositions containing highly diverseactive agents have already been proposed, such as, for example,2,4-diamino-6-piperidinopyrimidine 3-oxide (Minoxidil) described in thepatents U.S. Pat. No. 4,139,619 and U.S. Pat. No. 4,596,812 or the manyderivatives thereof such as those described, for example, in the patentapplications EP0353123, EP0356271, EP0408442, EP0522964, EP0420707,EP0459890 and EP0519819.

The Applicant found in a surprising manner that the C7 sugars andderivatives of formula (I), which will be defined below, have, amongothers, anti-inflammatory activity with a beneficial effect on theprotection of hair follicles and thus on the protection of the follicleafter each growth cycle. These C7 sugars and derivatives are,surprisingly, endowed with activity favorable to increased hair and naildensity. Thus, these compounds have a beneficial effect on the growth ofhuman hair but also on the growth of eyelashes and certain human hairsas well as on the growth of nails.

D-mannoheptulose, the first ketoheptose identified in 1916 by La Forge,of general formula (II):

is found in certain plants, in particular in alfalfa (Medicago sativaL.), avocado, fig (Ficus officinalis L.) stonecrop (Sedum spectabileBor.) and primula (Primula officinalis Jacq.). However, it is in avocadothat the highest D-mannoheptulose content is found. D-mannoheptulose hasalready been used in therapeutic applications. For example, the patentapplication WO95/03809 describes the use of D-mannoheptulose, as aglucokinase inhibitor, to inhibit the development of tumor cells, andapplication US2003/0092669 describes an oral dietary supplementcontaining D-mannoheptulose, which decreases insulin levels and whichthus enables weight loss.

Perseitol, a polyol form of D-mannoheptulose, of general formula (III):

is also found in avocado, in particular in the fruit or the seed.

According to the publication “Search for pharmacochemical leads fromtropical rainforest plants,” Hitotaka Shibuya et al., Pure Appl. Chem.,vol. 71, no. 6, pp 1109-1113, 1999, perseitol, associated with apotassium ion, inhibits the incorporation of 3H-leucine in tumor cellsof Ehrlich's ascites carcinoma.

The use of these sugars (perseitol and D-mannoheptulose) to stimulatethe synthesis of human beta-defensins (in particular HBD-2) has alreadybeen described (WO2005/115421). In particular, it was shown in thisapplication that avocado sugars induce HBD-2 synthesis without inducingthe synthesis of inflammatory mediators (which means that avocado sugarsare incapable of stimulating the inflammatory reaction, but which doesnot make it possible to foresee what one anti-inflammatory action orother might be). The use of these sugars to treat candidiasis andseborrheic dermatitis has also already been described (WO2008/025847).

The invention relates to a composition containing at least one C7-sugaror derivative of the following formula (I):

wherein:Ra represents a hydrogen atom and Rb represents —OR₂ or CRaRb representsa CO radical;R₁, R₂, R₃, R₄, R₅, R₆ and R₇ represent, independently of one another:

-   -   a hydrogen atom or    -   a —(CO)—R radical wherein R represents a saturated or        unsaturated hydrocarbon chain containing from 11 to 24 carbon        atoms, optionally substituted by one or more substituents        selected from the group comprising hydroxy radicals (—OH),        ethoxy radicals (—OC₂H₅) and an —SO₃M group with M representing        a hydrogen atom, an ammonium ion (NH₄ ⁺) or a metal ion; or    -   a —(CO)—R′ radical wherein R′ represents a saturated or        unsaturated hydrocarbon chain containing from 2 to 10 carbon        atoms, optionally substituted by one or more substituents        selected from the group comprising hydroxy radicals (—OH),        ethoxy radicals (—OC₂H₅) and an —SO₃M group with M representing        a hydrogen atom, an ammonium ion (NH₄ ⁺) or a metal ion;        and a pharmaceutically acceptable excipient for the treatment of        alopecia.

The term “alopecia” refers to both diffuse and localized hair loss. Itcovers in particular alopecia areata, diffuse hair loss, scarringalopecia, non-scarring alopecia and the disease of Quinquaud's disease.

Diffuse loss is characterized by thin and sparse hair over the entiretyof the scalp. It is often due to external factors such as stress, highfever, fatigue, overwork, medications, dietary imbalances, effects oflabor, significant surgical procedures, certain infectious diseases ortumors, pollution, etc. It is increasing quite rapidly, and affectsbetween 20% and 40% of women.

Alopecia areata is characterized by alopecia plaques due to inflammationof the hair root, following a self-defense reaction of the immunesystem.

Scarring alopecia is characterized by hair loss due to an inflammatorydisease of the skin (infection, inflammation, tumor, injury, burn, etc.)that permanently destroys the dermal papilla.

Non-scarring (non-cicatricial) alopecia is characterized by hair lossdue to hair follicle dysfunction, which prematurely interrupts thegrowth phase.

Quinquaud's decalvans folliculitis (also known as Quinquaud's disease orQuinquaud's syndrome) is an orphan disease characterized by inflammationof follicles at the root of hair of the head and body. Inflammation ofthese follicles causes hair loss (alopecia), with the hair falling outin delimited areas (plaques). It is an extremely disabling and verypainful disease.

The Applicant thus noted that the C7 sugars found in avocado, perseitoland mannoheptulose, as well as derivatives thereof from theesterification of one or more of the sugar's hydroxyl functional groups,advantageously with a fatty acid, are effective in the treatment ofalopecia and stimulate the growth of hair and nails.

The expression “hair and nails” refers to the hair, eyelashes, eyebrowsand nails, notably the hair and nails.

According to a first advantageous variant of the invention, the C7sugars are in a free form (the hydroxyl functional groups are notesterified). The composition thus contains a C7 sugar selected from thegroup comprising mannoheptulose, perseitol and mixtures thereof.

The source of D-mannoheptulose and/or perseitol can be an avocado sugarwater-soluble extract or sugars from another plant. Additionally,D-mannoheptulose and perseitol are available commercially (syntheticorigin). According to an advantageous variant of the invention, thesource of D-mannoheptulose and/or perseitol is an avocado sugarwater-soluble extract.

The avocado sugar water-soluble extract can be obtained directly fromany part of the avocado or avocado tree, such as the fruit, flesh orseed of the avocado or the leaves or roots of the avocado tree. It isalso possible to obtain the avocado sugar water-soluble extract from theby-products of the avocado processing industry, including but in no wayexhaustively: fresh avocado pulp, frozen pulp, dehydrated pulp, avocadooil cakes arising from oil extraction processes (mechanical extractionand/or by solvent using fruit dehydrated beforehand), de-oiled solidmatter arising from wet oil extraction processes (centrifugation),de-oiled solid matter arising from enzymatic avocado oil extractionprocesses, crude mashed avocado (guacamole) and solid waste from unitsthat manufacture such mashed avocado. The extract is advantageouslyobtained from the fresh fruit of the avocado tree. The fruits can beselected among the Hass, Fuerte, Ettinger, Bacon, Nabal, Anaheim, Lula,Reed, Zutano, Queen, Criola Selva, Mexicana Canta, Region Dschang, Hall,Booth, Peterson, and Collinson Redn varieties, more advantageously amongthe Hass, Fuerte and Reed varieties. Preferably, the Hass, Fuerte,Ettinger and Bacon varieties will be selected, and more advantageouslythe Hass and Fuerte varieties.

The fruit of the avocado tree is primarily composed of water, pulp, oiland seed. The proportions of these components are, like all natural andplant matter, highly variable. However, the mean composition datapresented in Table 1 below, expressed in percentages of fresh fruit, aregenerally accepted:

TABLE 1 Water 70-85% Proteins 1.5-4.5% Fats 12-23% Sugars 1.5-5%  Fibers1.1-1.6%

In fact, the avocado is not particularly polysaccharide-rich. However,the nature of soluble monosaccharides is quite specific, such asperseitol and D-mannoheptulose with 7 carbon atoms.

The avocado sugar water-soluble extract can be obtained by a methodcomprising the following successive steps:

-   -   an avocado oil cake is obtained, advantageously from avocado        fruit, through drying and extraction of the lipids (oil); after        which    -   total delipidation of said oil cake, then washing with water or        with a hydroalcoholic medium and then decanting and        centrifugation in order to recover a soluble fraction rich in C7        sugars (elimination of the cake);    -   demineralization on ionic resin of said soluble fraction        obtained in the preceding step; then    -   ultrafiltration at 10,000 daltons; and    -   as the case may be, concentration under vacuum and packaging.

The first step of the method consists in drying and then deoiling thefruit. Thus, after the fruit has been cut into thin slices, it may bedried by any of the techniques known to the person skilled in the art,among which mention may be made of hot air drying, lyophilization orosmotic drying. In general, the temperature during this drying step willbe advantageously maintained at or below 80° C., regardless of thetechnique used. In the context of the present method, for reasons ofease of implementation and cost, drying in ventilated dryers, in thinlayer and under a stream of hot air at a temperature between 70° C. and75° C., is preferred. The duration of this operation can vary between 5hours and 72 hours.

The lipids of the dried fruit are then extracted either mechanically inan expeller, or chemically with a solvent such as hexane in a Soxhletextractor or in a De Smet® continuous belt extractor, notably accordingto the method described in the application FR2843027, or by a methodusing supercritical CO₂. Among the main advantages of the method, theoil by-product can quite clearly be recovered directly. For this reasonmechanical lipid extraction is preferred. The dried and deoiled fruit,also called an oil cake, may then undergo the following steps:

-   -   total delipidation, notably with acetone and/or ethanol,    -   decanting and washing of the oil cake with water and/or a        hydroalcoholic mixture,    -   centrifugation, filtration and recovery of the soluble fraction        (elimination of the oil cake),    -   concentration,    -   demineralization by ion exchange,    -   ultrafiltration with a 10 kDa cutoff,    -   concentration under vacuum, addition of preservative and        packaging.

Generally, the final aqueous extract can contain by weight 0.1-20% drymatter, advantageously 1-10% dry matter, even more advantageously 3-5%dry matter. The content in C7 sugars, i.e., in D-mannoheptulose andperseitol, in the dry matter is advantageously between 50% and 100%,more particularly between 65% and 90% by weight, in relation to thetotal weight of the dry matter. The average analytical data for anaqueous solution with 5% dry extract, obtained by the method describedabove, are given in following Table 2:

TABLE 2 pH (¼ dilution) 3-5 Absorbance 420 nm Less than 0.200 (½dilution) 550 nm Less than 0.050 C7 sugars/dry matter 50-100%

The relative composition in sugars of the water-soluble extract, byweight in relation to the total weight of the dry matter of the extract,responds advantageously to the following criteria (relative compositiondetermined by high-performance liquid chromatography (HPLC)):

D-Mannoheptulose 0-100%, in particular 5-80%, Perseitol 0-100%, inparticular 5-80%, Sucrose less than 10%, Glucose less than 10%, Fructoseless than 10%.

The avocado sugar water-soluble extract contains advantageously, inrelation to the total weight of the dry matter, 10-80% by weightD-mannoheptulose, more advantageously 15-70% by weight D-mannoheptulose.The avocado sugar water-soluble extract contains advantageously, inrelation to the total weight of the dry matter, 20-80% by weightperseitol, more advantageously 25-70% by weight perseitol.

Preferably, the relative composition in sugars of the water-solubleextract, by weight in relation to the total weight of the dry matter ofthe extract, responds to the following criteria (relative compositiondetermined by HPLC):

D-Mannoheptulose 25-60%, Perseitol 25-60%, Sucrose less than 10%,Glucose less than 10%, Fructose less than 10%.

In a surprising manner, the Inventors noted a synergistic effect betweenD-mannoheptulose and/or perseitol and minority sugars (fructose,glucose, sucrose) present in the avocado sugar extract.

The extract obtained may be lyophilized in order to obtain a totallywater-soluble solid power (dry extract).

Optionally, the extract obtained can be fractioned into each purifiedsugar. This separation and purification can be carried out by any of thetechniques known to the person skilled in the art, among which mentionmay be made in a non-exhaustive manner of precipitation/filtration,recrystallization, or separation by chromatography such as the improvedsimulated moving bed (ISMB) method.

According to a second advantageous variant of the invention, the C7sugars, which are advantageously D-mannoheptulose and perseitol, are atleast partially esterified with a —(CO)—R radical wherein R represents asaturated or unsaturated hydrocarbon chain containing from 11 to 24carbon atoms, optionally substituted by one or more substituentsselected from the group comprising hydroxy radicals (—OH), ethoxyradicals (—OC₂H₅) and an —SO₃M group with M representing a hydrogenatom, an ammonium ion (NH₄ ⁺) or a metal ion. In particular, the C7sugars are at least partially esterified with a fatty acid residue. Thehydrocarbon chain can be linear or branched, and it is advantageouslylinear.

The radical R advantageously represents a fatty acid residue.

The fatty acids considered according to the invention are moreparticularly long-chain fatty acids, i.e., with more than 11 carbonatoms and notably more than 14 carbon atoms.

Their hydrocarbon chain can be saturated or contain one or more doublebonds. As examples of these fatty acids, mention may be made notably ofsaturated fatty acids such as palmitic (C₁₆), stearic (C₁₈), arachidic(C₂₀), behenic (C₂₂) and lignoceric (C₂₄) acids and unsaturated fattyacids such as palmitoleic (C₁₆), oleic (C₁₈), linoleic (C₁₈), linolenicin particular in its α and γ forms (C18), and arachidonic (C₂₀) acids.

In particular, the radical R is advantageously selected from the groupcomprising stearyl, linoleyl, oleyl, palmityl, lauryl, myristyl,arachidyl, behenyl, lauroleyl, myristoleyl, palmitoleyl, linolenyl inits α and γ forms, and/or arachidonyl radicals.

It is particularly advantageous to substitute the hydrocarbon chain withan —SO₃M group with M representing a hydrogen atom, an ammonium ion (NH₄⁺) or a metal ion (in particular sodium).

In derivatives of formula (I), the hydroxyl functional groups can besubstituted by the residue of the same fatty acid or by residues ofdifferent fatty acids.

The C7 sugar fatty acid derivatives can be obtained by esterificationreaction resulting from the bringing together, under suitableconditions, of one or more acids of formula HOOC—R(R having the samedefinition as in the preceding paragraphs) with commercially available(synthetic) D-mannoheptulose and/or perseitol or with the avocado sugarwater-soluble extract described above.

According to a third advantageous variant of the invention, the C7sugars, which are advantageously D-mannoheptulose and perseitol, are atleast partially esterified with a —(CO)—R′ radical wherein R′ representsa saturated or unsaturated hydrocarbon chain containing from 2 to 10carbon atoms, optionally substituted by one or more substituentsselected from the group comprising hydroxy radicals (—OH), ethoxyradicals (—OC₂H₅) and an —SO₃M group with M representing a hydrogenatom, an ammonium ion (NH₄ ⁺) or a metal ion. The hydrocarbon chain canbe linear or branched, and it is advantageously linear.

The radical R advantageously represents a residue of a short-chain acid,i.e., with less than 10 carbon atoms and notably less than 8 carbonatoms.

Their hydrocarbon chain can be saturated or contain one or more doublebonds. As an example of these acids, mention may be made notably ofacetic acid.

It is particularly advantageous to substitute the hydrocarbon chain withan —SO₃M group with M representing a hydrogen atom, an ammonium ion (NH₄⁺) or a metal ion (in particular sodium).

In derivatives of formula (I), the hydroxyl functional groups can besubstituted by the residue of the same acid or residues of differentacids.

The C7 sugar acid derivatives can be obtained by esterification reactionresulting from the bringing together, under suitable conditions, of oneor more acids of formula HOOC—R′ (R′ having the same definition as inthe preceding paragraphs) with commercially available (synthetic)D-mannoheptulose and/or perseitol or with the avocado sugarwater-soluble extract described above.

According to a fourth advantageous variant of the invention, the C7sugars, which are advantageously D-mannoheptulose and perseitol, are atleast partially esterified with a —(CO)—R radical and with a —(CO)—R′radical, R and R′ having the same definitions as those given in thesecond and third variants.

The C7 sugar acid derivatives can be obtained by esterification reactionresulting from the bringing together, under suitable conditions, of oneor more acids of formula HOOC—R and one or more acids of formula HOOC—R′with commercially available (synthetic) D-mannoheptulose and/orperseitol or with the avocado sugar water-soluble extract describedabove.

The derivatives obtained by the second, third or fourth variants arecalled D-mannoheptulose acid derivative or perseitol acid derivative,respectively.

In any one of the second, third or fourth variants, the ratio betweenthe number of ester functional groups of the compound of formula (I) andthe initial number of hydroxyl functional groups, or esterificationrate, for a sugar molecule, varies from 0.2 to 1. It is notably lessthan or equal to 0.6, and in particular less than or equal to 0.4.

The degree of esterification is controlled by reagent concentration,reaction duration and reaction temperature. It can be measured bychromatography, in particular by steric exclusion chromatography.

According to one or another of the four variants, the compositioncontains 0.001 to 30% by weight D-mannoheptulose or an acid derivativethereof, in relation to the total weight of said composition, and/or0.001 to 30% by weight perseitol or an acid derivative thereof, inrelation to the total weight of said composition. More particularly, thecomposition contains 0.002 to 5% by weight D-mannoheptulose or an acidderivative thereof, in relation to the total weight of said composition,and/or 0.002 to 5% by weight perseitol or an acid derivative thereof, inrelation to the total weight of said composition.

In the context of the present invention, the composition can furthercontain:

-   -   another active agent for treating alopecia; and/or    -   an anti-hair loss and/or hair and nail strengthening agent;        and/or    -   an anti-dandruff agent.

As an agent for treating alopecia, mention can be made notably of DHEAderivatives (7-hydroxy-DHEA and 7-keto-DHEA), taurine and derivativesthereof (EP1515712), 15-hydroxyprostaglandin dehydrogenase inhibitors(such as tetrazole compounds and others described in EP1358868),retinoic acid receptor agonists (such as the compounds described inEP829256), 4-aminopiperidine derivatives (EP1849455, EP1849456), N-oxidederivatives (EP1829523), thiazolidine-2,4-dione derivatives (EP1775294,EP1739083, EP1738742), 2-thioacetamide derivatives (EP1052576),styryl-pyrazole derivatives (EP1558203), pyridine-dicarboxylic acidderivatives (EP1352629), indole carboxylic derivatives (E9964852),2-amino-alkane-1,3-diol derivatives (EP790053), fructose, glucose and/orglobular proteins of grains or hydrolysates thereof (EP648107) andpyrimidine derivatives (EP522964, EP540629, EP459890, EP420707,EP376821, EP357484, EP347328, EP336813, E2336812, EP321951, EP319027,EP304665, EP2119475; -2,4-diaminopyrimidine-3-N-oxide).

The anti-hair loss and/or hair and nail strengthening agents areadvantageously phytosterols, isoflavones such as, for example, soyaisoflavones, RTH16®, Aminexil®, Minoxidil®, Viviscal®, retinol, zinc andderivatives thereof, neoruscine, vitamin E, vitamin B2, vitamin B3,vitamin B6, vitamin PP, vitamin B5 (panthenol, bepanthen, dexpanthenol),vitamin B8 (vitamin H or biotin), vitamin B9 (folic acid), alpha hydroxyacid, quinine and certain sulfur-containing amino acids such ascysteine, cystine and methionone. Mention may also be made of5-α-reductase inhibitors such as, for example, finasteride, dutasteride,Serenoa serrulata or repens, Cucurbita pepo extract or certainphytosterols. Mention may also be made of keratin, trace elements andmineral salts. Protein or lipid extracts from plants such as, forexample, Pfaffia, sage, lemon, ginseng, quinquina, jojoba, horsechestnut, honey, wheat, nettle, echinea, cophra or coconut extracts canalso be used.

The anti-dandruff agents (for the scalp) are advantageously selectedfrom Nasturtium extract, vitamin F, thymol, clay, zinc pyrithione,zinc-PCA, zinc gluconate, zinc sulfate, camphor, myrtle extract,salicylic acid, vitamin B5, climbazole, ichthyol, selenium andderivatives thereof, squash seed extract, Carthamus extract, Melaleucaoil extract, borage and Mimosa tenuiflora oil, propolis, kertyol,glycolic acid, keluamid, cyclopiroxolamine, piroctone olamine, capryloylglycine.

In the context of the present invention, the composition can furthercontain a dermatological active agent selected from the group comprisingmoisturizing active agents, keratin synthesis activators,keratoregulators, keratolytics, agents that repair the cutaneous barrier(cutaneous lipid synthesis activators or differentiation activators),healing agents, sebum-regulating agents, anti-irritant agents, soothingagents, anti-inflammatory agents, antioxidant agents, anti-aging agents,and mixtures thereof.

The most commonly used moisturizing active agents are glycerin orderivatives thereof, urea, pyrrolidone carboxylic acid and derivativesthereof, hyaluronic acid of any molecular weight, glycosaminoglycans andany other polysaccharides of marine, plant or biotechnological originsuch as, for example, xanthan gum, Fucogel®, certain fatty acids such aslauric acid, myristic acid, polyunsaturated and monounsaturated omega-3,-6, -7 and -9 fatty acids such as linoleic acid and palmitoleic acid,sunflower oleodistillate, avocado peptides, cupuagu butter.

The keratin synthesis activators that can be used in combination areadvantageously the retinoids, lupin peptides, key proteins of thestratum corneum or granulosum (keratins) and corneodesmosomes, quinoapeptides.

The most commonly used keratoregulating/keratolytic agents include:alpha-hydroxy acids (AHAs) of fruits (citric acid, glycolic acid, malicacid, lactic acid, etc.), AHA esters, combinations of AHAs with othermolecules such as the combination of malic acid and almond proteins(Keratolite®), the combination of glycolic acid or lactic acid witharginine or the combination of hydroxy acid with lipid molecules such asLHA® (lipo-hydroxy acid), amphoteric hydroxy acid complexes (AHCare),willow bark (Salix alba bark extract), azelaic acid and salts and estersthereof, salicylic acid and derivatives thereof such as capryloylsalicylic acid or in combination with other molecules such as thecombination of salicylic acid and polysaccharide (beta-hydroxy acid, orBHA), tazarotene, adapalene, as well as molecules of the retinoid familysuch as tretinoin, retinaldehyde, isotretinoin and retinol.

The healing/repairing agents that can be used in combination areadvantageously vitamin A, panthenol (vitamin B5), lupeol, maca peptideextract, quinoa peptide extract, arabinogalactan, zinc oxide, magnesium,silicon, madecassic or asiatic acid, dextran sulfate, coenzyme Q10,glucosamine and derivatives thereof, chondroitin sulfate and on thewhole glycosaminoglycans (GAGs), dextran sulfate, ceramides,cholesterol, squalane, phospholipids, fermented or unfermented soyapeptides, plant peptides, marine, plant or biotechnologicalpolysaccharides such as algae extracts or fern extracts, trace elements,extracts of tannin-rich plants such as tannins derived from gallic acidcalled gallic or hydrolysable tannins, initially found in oak gall, andcatechin tannins resulting from the polymerization of flavan units whosemodel is provided by the catechu (Acacia catechu). The trace elementsthat can be used are advantageously selected from the group comprised ofcopper, magnesium, manganese, chromium, selenium, silicon, zinc andmixtures thereof. Sunflower concentrates, more advantageously linoleicsunflower concentrates may also be used, such as the active agent soldby Laboratoires Expanscience, Soline®, vegetable oil unsaponifiablessuch as Avocadofurane®, PPAR agonists (rosiglitazone, pioglitazone), RXRand LXR.

The sebum-regulating agents that can be used in combination areadvantageously selected from the group comprising 5-α-reductaseinhibitors such as, for example, the active agent 5-α Avocuta®. Zinc(and gluconate salts thereof, salicylate and pyroglutamic acid) also hassebum-suppressing activity. Mention may also be made of spironolactone,an anti-androgen and aldosterone antagonist, which significantly reducesthe sebum secretion rate after 12 weeks of application. Other moleculessuch as, for example, Cucurbita pepo, extracted from pumpkin seeds,squash seed oil and palm cabbage limit sebum production by inhibiting5-α-reductase transcription and activity. Other sebum-regulating agentsof lipid origin that act on sebum quality, such as linoleic acid, are ofinterest.

Anti-inflammatory, anti-irritant and soothing agents limit theinflammatory reaction led via cytokines or mediators of arachidonic acidmetabolism and have soothing and anti-irritant properties. The mosttraditional are glycyrrhetinic acid (licorice derivatives) and salts andesters thereof, lipoic acid, beta-carotene, vitamin B3 (niacinamide,nicotinamide), vitamin E, vitamin C, vitamin B12, flavonoids (green tea,quercetin, etc.), lycopene or lutein, avocado oleodistillate,arabinogalactan, lupin peptides, lupin total extract, quinoa peptideextract, Cycloceramide® (oxazoline derivative, compound called OX-100 inWO03/055463), isoflavones such as, for example, genistein/genistin,daidzein/daidzin, spring water or thermal spring water (eau d'Avène, eaude la Roche Posay, eau de Saint Gervais, eau d'Uriage, eau de Gamarde),goji (Lycium barbarum) extracts, plant amino acid peptides or complexes,topical dapsone, or steroidal anti-inflammatory drugs such ascorticosteroids, or non-steroidal anti-inflammatory drugs (NSAIDs).

The term “antioxidant” refers to a molecule that decreases or preventsthe oxidation of other chemical substances. The antioxidants that can beused in combination are advantageously selected from the group comprisedof thiols and phenols, licorice derivatives such as glycyrrhetinic acidand salts and esters thereof, alpha-bisabolol, Ginkgo biloba extract,Calendula extract, Cycloceramide® (oxazoline derivative), avocadopeptides, trace elements such as copper, zinc and selenium, lipoic acid,vitamin B12, vitamin B3 (niacinamide, nicotinamide), vitamin C, vitaminE, coenzyme Q10, krill, glutathione, butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), lycopene or lutein, beta-carotene, thelarge family of polyphenols such as tannins, phenolic acids,anthocyanins, flavonoids such as, for example, extracts of green tea, ofred berries, of cocoa, of grapes, of Passiflora incarnata or of Citrus,or isoflavones such as, for example, genistein/genistin anddaidzein/daidzin. The group of antioxidants further includesanti-glycation agents such as carnosine or certain peptides,N-acetyl-cysteine, as well as antioxidant or free-radical scavengingenzymes such as superoxide dismutase (SOD), catalase, glutathioneperoxidase, thioredoxin reductase and agonists thereof.

The anti-aging agents are advantageously antioxidants and in particularvitamin C, vitamin A, retinol, retinal, hyaluronic acid of any molecularweight, Avocadofurane®, lupin peptides and maca peptide extract.

In the context of the present invention, the composition can furthercontain an active agent selected from the group comprising prebioticsand probiotics, antibacterial agents, antifungal compounds,preservatives, immunomodulators, growth factors and inorganic or organicsun filters and screens (pigmentary or ultrafine).

The prebiotics and probiotics that can be used in combination areadvantageously trans-galacto-oligosaccharides, fructans orfructo-oligosaccharides for prebiotics and probiotics belonging togenera Lactobacilli and Bifidobacteria.

The antifungal compounds that can be used in combination areadvantageously econazole and ketoconazole.

The preservatives and antibacterial agents that can be used incombination are, for example, those generally used in cosmetics ornutraceuticals, molecules with anti-bacterial activity(pseudo-preservatives) such as caprylic derivatives like, for example,capryloyl glycine and glyceryl caprylate, such as hexanediol and sodiumlevulinate, zinc and copper derivatives (gluconate and PCA),phytosphingosine and derivatives thereof, benzoyl peroxide, piroctoneolamine, zinc pyrithione and selenium sulfide. The antisepticpreservatives that can be used in combination are, for example,triclosan, chlorhexidine and quaternary ammonium.

The immunomodulators that can be used in combination are advantageouslytacrolimus, pimecrolimus and oxazolines. The oxazolines that can be usedin combination are advantageously oxazolines selected from the groupcomprised of 2-undecyl-4-hydroxymethyl-4-methyl-1,3-oxazoline,2-undecyl-4,4-dimethyl-1,3-oxazoline,(E)-4,4-dimethyl-2-heptadec-8-enyl-1,3-oxazoline,4-hydroxymethyl-4-methyl-2-heptadecyl-1,3-oxazoline,(E)-4-hydroxymethyl-4-methyl-2-heptadec-8-enyl-1,3-oxazoline and2-undecyl-4-ethyl-4-hydroxymethyl-1,3-oxazoline. Even moreadvantageously, said oxazoline is 2-undecyl-4,4-dimethyl-1,3-oxazoline,called OX-100 or Cycloceramide®.

The growth factors that may be used in combination are advantageouslybecaplermin and transforming growth factor-β (TGF-β), EGF, NGF and VEGF.

As examples of sun protection active agents, mention may be made notablyof titanium dioxide, zinc oxide, methylene bis-benzotriazolyltetramethylbutylphenol (brand name: Tinosorb M) andbis-ethylhexyloxyphenol methoxyphenyl triazine (brand name: Tinosorb S),octocrylene, butyl methoxydibenzoylmethane, terephthalylidene dicamphorsulfonic acid, 4-methylbenzylidene camphor, benzophenone, ethylhexylmethoxycinnamate, ethylhexyl dimethyl PABA and diethylhexyl butamidotriazone.

In the context of the present invention, the composition can furthercontain one or more (in particular two, three or four) active agentsselected from the group comprising:

-   -   a Schisandra sphenanthera fruit extract, in particular a        Schisandra sphenanthera peptide and sugar extract;    -   an avocado peptide extract, in particular that described in        request WO2005/105123;    -   an avocado oil (see international applications WO2004/012496,        WO2004/012752, WO2004/016106, WO2007/057439);    -   avocado furans, in particular Avocadofurane® (avocado furans        obtained by the method described in international application        WO01/21605);    -   a fatty ester whose fatty chain is a linear C₇-C₃₀ hydrocarbon        chain comprising between 0 and 2 ethylene unsaturations and        which can be substituted by 1 to 3 hydroxy groups and/or 1 to 3        ester functional groups in addition to the principal ester        functional group, in particular 5-α Avocuta® (butyl avocadate),        to inhibit 5-α reductase (see WO01/52837 and WO02/06205);    -   avocado and/or soya unsaponifiables, advantageously a mixture of        avocado furan unsaponifiables and soya unsaponifiables, in a        ratio of roughly 1:3-2:3, respectively. The avocado and soya        unsaponifiables are even more advantageously the product        Piascledine®, sold by Laboratoires Expanscience;    -   a sunflower oleodistillate, even more advantageously with        linoleic sunflower concentrates, such as the active agent sold        by Laboratoires Expanscience, Soline® (see international        application WO01/21150);    -   lupeol (FR2822821, FR2857596);    -   lupin peptides such as obtained according to the method        described in application WO2005/102259;    -   a total lupin extract (see international application        WO2005/102259);    -   a lupin oil, advantageously sweet white lupin oil, such as that        described in international application WO98/47479;    -   a maca peptide extract (see international application        WO2004/112742);    -   an oxazoline, in particular 2-undecyl-4,4-dimethyl-1,3-oxazoline        (Cycloceramide®) as described in international applications        WO2004050052, WO2004050079;    -   rice peptides (as described in international application        WO2008/009709);    -   a quinoa extract, in particular a quinoa peptide extract        (WO2008/080974);    -   cupuaçu butter;    -   a rapeseed or corn concentrate.

The composition is advantageously intended for topical or oraladministration.

According to an advantageous variant, the compositions of the inventionare suited to the topical administration on the scalp and includeshampoos, gels, emulsions, milks, lotions, oils, aqueous orhydroalcoholic or glycolic solutions, powders, sprays or any otherproduct for external application, such as, for example, varnishes forapplication on the nails.

The invention further relates to a method of cosmetic treatment of hairand nails, in particular the hair, intended to stimulate the growththereof and/or to slow the loss thereof, characterized in that itconsists in administering a cosmetic composition containing at least onederivative of formula (I) such as defined according to any of the fourvariants, optionally in combination with one or more of the activeagents cited above.

The invention further relates to a cosmetic care method of the hairand/or eyelashes and/or nails, in order to improve the condition thereofand/or the appearance thereof, characterized in that it consists inadministering a cosmetic composition containing at least one derivativeof formula (I) such as defined according to any of the four variants,optionally in combination with one or more of the active agents citedabove.

According to this cosmetic care method, the cosmetic compositionadvantageously is applied to the hair and/or eyelashes and/or nails andthen left in contact with the hair and/or eyelashes and/or nails andthen optionally rinsed out.

According to this cosmetic care method, the cosmetic composition isadvantageously administered orally, preferably in the form of soft orhard capsules, tablets, cereal bars or beverages. The minimum andmaximum daily doses are advantageously between 10 mg and 250 mg,depending on the indication: for preventive treatment, one dose one ortwo times/day for two months (or 10-150 mg/day) is recommended and forcurative treatment, one dose two, four or six times/day for one month(or 50-250 mg/day) is recommended.

The following examples illustrate the invention but are not restrictive.

EXAMPLE 1 Preparation of an Avocado Sugar Water-Soluable Extract

Fifty kilograms of fresh avocados, the Hass variety, are cut into thinslices 2-5 mm thick, seed included, using a circular-blade slicer. Thedrying apparatus is a temperature controlled hot air drying oven. Thesliced avocados are distributed in a thickness of 4-5 cm on stackedracks. Drying is for 48 hours at a temperature of 80° C. Once dried, thefruits are subjected to cold pressing. This operation is carried out ona small Komet® laboratory press.

Four kilograms of delipidated fruits (oil cake) are cold crushed andthen extracted at reflux in the presence of 25 liters of ethanol. Thefat-depleted powder is then recovered by filtration on a Büchner funneland oven dried at 50° C. for 5 hours.

The oil cake is washed with demineralized water (10 liters) and thenseparated by centrifugation. The solid fraction is taken up to bepurified and concentrated according to the following procedure:

-   -   Demineralization using ion exchange resins: demineralization of        heptuloses by passage on OH⁻ resins and then on H⁺ resin.    -   Ultrafiltration at 10,000 Da: ultrafiltration is carried out        with a system equipped with four membranes with a 10 kDa        cut-off.    -   Concentration under vacuum: the purified extract is concentrated        using a vacuum evaporator until a roughly 4% dry matter content        is obtained.    -   Packaging: the concentrated extract is adjusted to 5% dry matter        and preservative is added, then it is sterile filtered on a 0.2        μm cut-off membrane and packaged.

Following Table 3 gives the composition of the C7 avocado sugar extract,with 5% dry matter, prepared according to the method described above:

TABLE 3 Pale yellow Appearance solution Analytic criteria Dry matter 5%pH (¼ dilution) 7.0 Absorbance at 420 nm (¼ dilution) 0.013 Absorbanceat 550 nm (¼ dilution) 0.003 Composition (%/dry matter) Sucrose 3.0Glucose 7.5 D-Mannoheptulose 40.0 Fructose 10.6 Perseitol 28.8

According to this same method, two other extracts were prepared, whosepH, absorbance and C7 sugar content values are given in following Table4. C7 sugar content corresponds to the sum of perseitol andD-mannoheptulose analyzed by HPLC.

TABLE 4 Batch 1 2 Dry matter 5% 5% pH (¼ dilution) 5.9 5.4 Absorbance420 nm 0.054 0.076 (¼ dilution) 550 nm 0.004 0.032 C7 sugars/dry matter80.5 83.4

EXAMPLE 2 Evaluation of Anti-Inflammatory Properties of Avocado Sugars(Obtained in Example 1) In Vitro—Keratinocytes Stressed with LPS

We evaluated the capacity to modulate the inflammatory response of theavocado sugars obtained according to Example 1, hereafter called AV119,in human primary keratinocytes stressed with LPS (lipopolysaccharide).

Methodology

The cells were pretreated with 0.1% AV119 for 24 h and successively with10 μg/ml of LPS for 24 h. In another series of experiments, thekeratinocytes were pretreated with 30 μM calpain and successively with10 μg/ml LPS for 24 h. Calpain is a specific inhibitor of thetranscription factor NFκB, a key element of the inflammatory cascade. Acontrol of keratinocytes treated only with AV119 was prepared.

Expression of mRNA for the cytokines IL-6, IL-8, IL-1α and TNF-α wasanalyzed by real-time PCR and protein production and release wereanalyzed by ELISA in the culture supernatants. Moreover, ICAM-1expression and production were also analyzed. Finally, IκBphosphorylation was analyzed to measure the activation of transcriptionfactor NFκB.

Real-Time PCR:

Total RNA was extracted with the High Pure RNA Isolation Kit (RocheDiagnostics) according to the manufacturer's recommendations. 1 ng ofRNA was reverse-transcribed into complementary DNA (cDNA) (ExpandReverse Transcriptase, Roche Diagnostics) using hexamer primers (randomhexamers, Roche Diagnostics), at 42° C. for 45 min, according to themanufacturer's instructions. Real-time PCR was carried out using SYBRGreen technology with the LC Fast Start DNA Master SYBR Green kit (RocheDiagnostics) (LightCycler 2.0 Instrument). The melting curve wasanalyzed at the end of each amplification to ensure the absence ofnon-specific reaction products. Quantification rests on the measure ofthreshold cycles (CT), which are measured at the beginning of theexponential phase of the reaction and on the normalization of theinternal standard curve obtained with the reference gene beta-actin.

ELISA Test for IL-6, IL-8, IL-1α, TNF-α and ICAM-1:

A standard protocol was used for the ELISA tests (PhoenixPharmaceuticals, Inc.).

Western Blot:

Proteins were extracted from the keratinocytes by cold homogenization inlysis buffer (50 mM HEPES pH 7.5, 150 mM NaCl, 1% glycerol, 1% Triton,1.5 mM MgCl₂, 5 mM EGTA) supplemented with 20 mM sodium pyrophosphate,10 mM sodium orthovanadate and 25 mM NaF and protease inhibitors(aprotinin, phenylmethanesulfonyl fluoride (PMSF)). Protein level wasquantified by the Bradford method. 5 μg of protein was deposited on a12.5% or 7% polyacrylamide electrophoresis gel and was transferred onnitrocellulose membranes. The membranes were saturated overnight with 5%nonfat milk and then incubated with 1 μg/ml anti-IκB-α polyclonalantibody (Santa Cruz) overnight at 4° C., or with 1 μg/mlanti-phospho-IκB-α monoclonal antibody (Stressgen, Milan, Italy) for 2 hat room temperature. After rinsing, the membranes were developed by theperoxidase/chemiluminescence system (ECL System, Amersham BiosciencesBiotech, Milan, Italy).

Results

TABLE 5 Gene expression (mRNA, real-time PCR) of pro- inflammatorycytokines IL-6, IL-8, IL-1α and TNF-α in keratinocytes stresses with LPSand treated with AV119 IL-6 IL-8 IL-1α TNF-α 0.1% AV119 3.0 1.5 2.0 1.9LPS 54.5 54.1 71.5 68.0 LPS + 0.1% AV119 15.3 10.0 7.2 17.7 LPS +calpain 1 5.0 5.0 6.0 6.5

TABLE 6 Protein production (ELISA) of pro-inflammatory cytokines IL-6,IL-8, IL-1α and TNF-α in keratinocytes stressed with LPS and treatedwith AV119 IL-6 IL-8 IL-1α TNF-α Control 2 1.5 2.5 1.9 0.1% AV119 4 3.53 2.8 LPS 76 85 82 96.0 LPS + 0.1% AV119 13 10 11 17.7 LPS + calpain 1 98 5 6.5

TABLE 7 Gene expression (mRNA, real-time PCR) of adhesion moleculeICAM-1 in keratinocytes stressed with LPS and treated with AV119 ICAM-11% AV119 1.0 LPS 53.2 LPS + 1% AV119 20.7 LPS + calpain 1 7.0

TABLE 8 Protein production (ELISA) of adhesion molecule ICAM-1 inkeratinocytes stressed with LPS and treated with AV119 ICAM-1 Control2.0 1% AV119 4.0 LPS 85 LPS + 1% AV119 34.0 LPS + calpain 1 7.0

The transcription factor NFκB is in inactive form in the cell cytoplasmwhen the IκB subunit contained within it is dephosphorylated. Thus, IκBphosphorylation activates the factor NFκB. Activated NFκB is thentranslocated into the nucleus where it interacts with the specificsequences of the genes it regulates and thus activates theirtranscription. NFκB regulates many inflammation genes.

In the experiment, LPS strongly induced IκB phosphorylation and thusactivation of transcription factor NFκB, whereas AV119 inhibits IκBphosphorylation quite clearly and with the same intensity as the NFκBinhibitor, calpain. The avocado sugars AV119, in this experiment,demonstrate their capacity to inhibit the transcription factor NFκB.

Conclusion

The results clearly show that the avocado sugars AV119 are capable ofinhibiting the inflammatory response induced by LPS in the same way asthe NFκB inhibitor (calpain) by decreasing cytokines IL-6, IL-8, IL-1αand TNF-α on the mRNA (Table 5) and protein (Table 6) levels. Inaddition, the sugars AV119 are also capable of inhibiting the adhesionmolecule ICAM-1 on the mRNA (Table 7) and protein (Table 8) levels.

Moreover, the results show that LPS is capable of inducing IκBactivation by phosphorylating it whereas avocado sugars, just as thespecific NFκB inhibitor (calpain), are capable of inhibiting IκBphosphorylation and thus its activation (Figure 1). Thus, by limitingIκB activation, avocado sugars limit activation of the transcriptionfactor NFκB and thus inhibit activation of the inflammatory response.

EXAMPLE 3 Evaluation of Anti-Inflammatory Properties of Avocado Sugars(Obtained in Example 1) In Vitro—Keratinocytes Stressed with PMA

We evaluated the capacity to modulate the inflammatory response of theavocado sugars obtained according to Example 1, hereafter called AV119,in human primary keratinocytes stressed with PMA (phorbol myristicacetate).

Methodology

At day 0 (D0), normal human epidermal keratinocytes (NHEK) are seeded inhydrocortisone-free KGM2 medium.

At subconfluence (at D1), the NHEK are rinsed with PBS and thenpretreated with 0.005% and 0.05% avocado sugars AV119 or 0.1 μMdexamethasone (positive control) (Sigma, product D4902) inhydrocortisone-free KGM2 medium.

Twenty-four hours later, the NHEK are treated overnight with 10 μg/mlPMA (phorbol myristate acetate).

After incubation, the culture supernatants are collected and stored at−80° C. awaiting the cytokine (IL-1β, TNF-α, IL-8) ELISA (R&D Systemskits).

In parallel, the number of living cells is determined by a neutral redtest.

The quantity of cytokine assayed for each condition (concentration inpg/ml, or OD₄₅₀) is reduced to the number of living cells by dividing bythe OD₅₄₀ value obtained at the end of the neutral red test.

The results are compared statistically using a one way ANOVA followed bya Tukey's test.

Results

TABLE 9 Analysis of IL-1β release by keratinocytes stressed with PMA andtreated with AV119 IL-1β % in pg/ml/OD₄₅₀ relation to Conditions (mean ±SD) Significance the control Control 0.729 ± 0.440 without PMA PMA10.930 ± 0.190  $$$ 1399 Dexamethasone 3.232 ± 0.329 *** −70 0.005%AV119 4.163 ± 0.723 *** −62 0.05% AV119 3.169 ± 1.141 *** −71 $$$ p <0.001: increase by PMA in relation to the untreated control (withoutPMA) *** p < 0.001: inhibition by dexamethasone or AV119 in relation toPMA

TABLE 10 Analysis of TNF-α release keratinocytes stressed with PMA andtreated with AV119 % in TNF-α relation pg/ml/OD₄₅₀ to the Conditions(mean ± SD) Significance control Control without 0.049 ± 0.006 PMA PMA0.584 ± 0.079 $$$ 1091 Dexamethasone 0.328 ± 0.007 −44 0.005% AV1190.311 ± 0.019 * −47 0.05% AV119 0.385 ± 0.059 −34 $$$ p < 0.001:increase by PMA in relation to the untreated control (without PMA) * p <0.01: inhibition by dexamethasone or AV119 in relation to PMA

TABLE 11 Analysis of IL-8 release by keratinocytes stressed with PMA andtreated with AV119 % in IL-8 relation pg/ml/OD₄₅₀ to the Conditions(mean ± SD) Significance control Control without 0.158 ± 0.064 PMA PMA1.765 ± 0.305 $$$ 1017 Dexamethasone 0.790 ± 0.089 *** −55 0.005% AV1190.739 ± 0.037 *** −58 0.05% AV119 0.792 ± 0.170 *** −55 $$$ p < 0.001:increase by PMA in relation to the untreated control (without PMA) *** p< 0.001: inhibition by dexamethasone or AV119 in relation to PMA

Conclusion

In this study, we demonstrated that PMA significantly induced primarymediators of inflammation (IL-1β, TNF-α) as well as the secondarymediator, the chemokine IL-8. We clearly demonstrated that the avocadosugars AV119 inhibit pro-inflammatory mediators strongly and in a mannercomparable to dexamethasone, which known for its anti-inflammatoryproperties.

EXAMPLE 4 Examples of Formulations Topical Application

Keratinizing Fluid

Raw material/brand name % Cetyl alcohol 1-5% Silicone 345 1-5%Antioxidant 0-1% Purified water qsp 100% Cetrimonium chloride 0-5%Avocado sugars (Example 1) 0-5% Maca peptide extract 0-5% Hydrolyzedwheat protein 0-1% Preservative 0-2% Fragrance 0-1% pH adjuster 0-1%

Regulating Shampoo

Raw material/brand name % Purified water qsp 100% Lauroamphoacetate 5-20% Cocoglucoside  5-20% PEG 6000 distearate 1-5% Preservatives 0-2%Esterified avocado sugars (Example 2) 0-5% Cycloceramides 0-5% Zincpyrithione 0-1% pH adjuster 0-1% Sequestrant 0-1% Fragrance 0-1%

Antidandruff Shampoo

Raw material/brand name % Purified water qsp 100% Lauroamphoacetate 5-20% Cocoglucoside  5-20% PEG 6000 distearate 1-5% Preservatives 0-2%Avocado sugars (Example 1) 0-5% Sunflower oleodistillate 0-5% pHadjuster 0-1% Sequestrant 0-1% Fragrance 0-1%

Conditioner

Raw material/brand name % Cetearyl alcohol/ceteareth-33 1-5%Quaternium-82 0-2% Purified water qsp 100% Hydrolyzed wheat protein 0-5%Preservatives 0-2% pH adjuster 0-1% Fragrance 0-1% Lupin total extract0-5% Esterified avocado sugars (Example 2) 0-5%

Capillary Lotion

Raw material/brand name % Purified water qsp 100% Methyl propanediol 5-20% Preservative 0-2% pH adjuster 0-1% Fragrance 0-1% Avocado sugars(Example 1) 0-5% Lupeol 0-5% Ethylhexyl cocoate 0-5% PEG-40 castor oil0-5%

Hairspray

Raw material/brand name % Purified water qsp 100% Sodium magnesiumsilicate 1-5% Ethanol  5-20% pH adjuster 0-1% Fragrance 0-1% Avocadosugars (Example 1) 0-5% PVP 0-5% PEG-40 castor oil 0-5%

Hair Gel

Raw material/brand name % Purified water qsp 100% Carbomer 0-5% Silicone 0-10% pH adjuster 0-2% Fragrance 0-1% Avocado sugars (Example 1) 0-5%Hydrolyzed wheat protein 0-5% PEG-40 castor oil 0-5%

Styling Gel

Raw material/brand name % Purified water qsp 100% Carbomer 0-5%AMP-acrylates/allyl methacrylate copolymer  0-10% pH adjuster 0-2%Fragrance 0-1% Avocado sugars (Example 1) 0-5% PEG-40 castor oil 0-5%

Varnish for Fragile and Brittle Nails

Raw material/brand name % Acrylate copolymer 15-30% Ethanol qsp 100%Acetone  5-20% Avocado sugars (Example 1) 0-5%

EXAMPLE 5 Examples of Formulations—Compositions for Oral Administration

1) Anti-Hair Loss Composition in the Form of Soft Capsules

A-Composition 1

Avocado sugars (Example 1) 30 mg Squash seed oil 100 mg Methionine 100mg Vitamin of group B (B1, B2, qsp 100% RDA B3, B5, B6, B9, B12) Znchelate qsp 100% RDA Fe chelate qsp 100% RDA Beeswax Soya lecithinAlimentary gelatin Glycerin

This composition is administered as two 500 mg capsules per day.

B-Composition 2

Avocado sugars (Example 2) 40 mg Cereal oil rich in ceramides 300 mg andpolar lipids Lupin oil 50 mg Vitamin E qsp 100% RDA Vitamin C  qsp 50%RDA Beeswax Soya lecithin Alimentary gelatin Glycerin

This composition is administered as four to six 500 mg capsules per day.

2) Hair Fortifying Tablets

Avocado sugars (Example 1) 40 mg Cereal extracts (corn, buckwheat,millet, 200 mg spelt) rich in sulfur-containing amino acids Vitamin Cqsp 100% RDA Fish cartilage glycosaminoglycans 200 mg Glucidex IT 19(compression agent) qsp one 800 mg tablet

This composition is administered as two to six tablets per day.

3) Nail Fortifying Formula

Avocado sugars (Example 1) 150 mg Cereal extracts (corn, buckwheat,millet, 200 mg spelt) rich in sulfur amino acids Zn in chelate formBamboo extract rich in silicic acid 100 mg Fish cartilageglycosaminoglycans 200 mg Fruit flavor (citrus fruits, red berries), qspone potassium acesulfame, Glucidex IT 19 2000 mg tablet (compressionagent)This composition is administered once per day.4) Anti-Hair Loss Powder Stick

Avocado sugars (Example 1) 100 mg Polyphenol-rich tea extract 100 mgOPC-rich grape extract 50 mg Hop extract rich in 8-prenylnaringenin 50mg Xanthan gum Sodium ascorbate MaltodextrinSaid composition is administered twice per day.5) Chocolate-Flavored Nail-Strengthening Cereal Bar

Avocado sugars (Example 1) 150 mg Glycosaminoglycans 100 mg Hyaluronicacid 500 mg Horsetail extract rich in silicic acid 100 mg Naturaltocopherols 4 mg Dark chocolate, oligofructose, sugar, fructose qsp onesyrup, fat-reduced cocoa, crunchy cereals, 50 g bar powdered skim milk,almonds, glycerol, sorbitol, vegetable oils, glucose syrup, flavoring,sweetened condensed milk, soya lecithin, fatty acid mono- anddiglycerides, caramelized syrup, maltodextrin, salt, potassium sorbate,alpha-tocopherolThis composition is administered once per day.6) Vanilla-Flavored Anti-Hair Loss Cereal Bar

Esterified avocado sugars (Example 2) 150 mg Cereal extracts (corn,buckwheat, millet, 200 mg spelt) rich in sulfur-containing amino acidsFish cartilage glycosaminoglycans 500 mg Protein hydrolysate rich intype-II collagen 500 mg Polyphenol-rich green tea extract 200 mgOligofructose, sugar, fructose syrup, crunchy qsp one cereals, powderedskim milk, almonds, glycerol, 50 g bar sorbitol, vegetable oils, glucosesyrup, flavoring, sweetened condensed milk, soya lecithin, fatty acidmono- and diglycerides, caramelized syrup, maltodextrin, salt, potassiumsorbate, alpha-tocopherolThis composition is administered once per day.7) Hard Nails Praline-Flavored Lacteal Beverage

Avocado sugars (Example 1) 150 mg Polyphenol-rich green tea extract 100mg Vitamin of group B (B1, B2, B3, B5, B6, B9, B12) qsp 100% RDA Zn, Mg,Se qsp 100% RDA Hyaluronic acid 200 mg Bamboo extract rich in silicicacid 200 mg Skimmed milk powder, flavoring, fructose, egg white, hazelnuts, sugar, caramel, beta-carotene, xanthan gum, aspartame, potassiumacesulfame, soya lecithin, maltodextrin

This composition is administered once per day.

The invention claimed is:
 1. A method to stimulate the growth of hairand/or to slow the loss of the hair, comprising administering to aperson suffering from alopecia a composition comprising amannoheptulose, a perseitol, or a mixture thereof and an acceptableexcipient, wherein the source of mannoheptulose and perseitol iscompletely delipidated avocado fruit.
 2. The method of claim 1, whereinthe composition is topically applied to the hair and/or eyelashes andthen left in contact with the hair and/or eyelashes.
 3. The method ofclaim 1, wherein the composition is topically applied to the hair and/oreyelashes and then left in contact with the hair and/or eyelashes andrinsed.
 4. The method of claim 1, wherein the composition isadministered orally.
 5. The method of claim 4, wherein the compositionis administered in the form of soft or hard capsules, tablets, cerealbars or beverages.
 6. The method of claim 1, wherein said compositioncontains 0.001 to 30% by weight D-mannoheptulose, in relation to thetotal weight of said composition, and/or 0.001 to 30% by weightperseitol, in relation to the total weight of said composition.
 7. Themethod of claim 6, wherein the source of D-mannoheptulose and/orperseitol is an avocado sugar water-soluble extract.
 8. The method ofclaim 7, wherein the avocado sugar water-soluble extract is obtained bya method comprising the following successive steps: an avocado oil cakeis obtained through drying and extraction of the lipids; after whichgrinding and extraction with water or with hydroalcoholic mixture ofsaid oil cake, then decanting and centrifugation in order to recover asoluble fraction rich in C7 sugars (elimination of the cake);demineralization on ionic resin of said soluble fraction obtained in thepreceding step; then ultrafiltration at 10,000 daltons; andconcentration under vacuum and packaging.
 9. The method of claim 8,wherein the avocado oil cake is obtained from avocado fruit.
 10. Themethod of claim 9, wherein the avocado sugar water-soluble extractcontains by weight in relation to the total weight of the dry matter ofthe extract (relative composition determined by HPLC): D-Mannoheptulose5-80% Perseitol 5-80% Sucrose less than 10% Glucose less than 10%, andFructose less than 10%.
 11. The method of claim 1, wherein saidcomposition further contains another active agent for treating alopecia,and/or an anti-hair loss and/or hair and nail strengthening agent,and/or an anti-dandruff agent.
 12. The method of claim 11, wherein saidcomposition further contains a dermatological active agent selected fromthe group comprising moisturizing active agents, keratin synthesisactivators, keratoregulators, keratolytics, agents that repair thecutaneous barrier, healing agents, sebum-regulating agents,anti-irritant agents, soothing agents, anti-inflammatory agents,antioxidant agents, anti-aging agents, and mixtures thereof.
 13. Themethod of claim 11, wherein said composition further contains an activeagent selected from the group comprising prebiotics and probiotics,antibacterial agents, antifungal compounds, preservatives,immunomodulators, growth factors and inorganic or organic sun filtersand screens (pigmentary or ultrafine).
 14. The method of claim 11,wherein said composition further contains an active agent selected fromthe group comprising: a Schisandra sphenanthera fruit extract; anavocado peptide extract; an avocado oil; avocado furans; a fatty esterwhose fatty chain is a linear C₇-C₃₀ hydrocarbon chain comprisingbetween 0 and 2 ethylene unsaturations and which can be substituted by 1to 3 hydroxy groups and/or 1 to 3 ester functional groups in addition tothe principal ester functional group; avocado and/or soyaunsaponifiables; a sunflower oleodistillate; lupeol; lupin peptides; atotal lupin extract; a lupin oil; a maca peptide extract; an oxazoline;a quinoa extract; rice peptides; cupuaçu butter; and a rapeseed or cornconcentrate.
 15. The method of claim 14, wherein the Schisandrasphenanthera is a Schisandra sphenanthera peptide and sugar extract. 16.The method of claim 14, wherein the fatty ester is butyl avocadate. 17.The method of claim 14, wherein the oxazoline is2-undecyl-4,4-dimethyl-1,3-oxazoline.
 18. The method of claim 14,wherein the quinoa extract is a quinoa peptide extract.